P1145: PRELIMINARY RESULTS OF PENPULIMAB COMBINED WITH RMA(RITUXIMAB, METHOTREXATE, AND CYTARABINE) FOR NEWLY DIAGNOSED PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA (PCNSL)
Authors: Haorui Shen, Jia-Zhu Wu, Jinhua Liang, Hua Yin, LI Wang, Jianyong LI, Wei Xu
Journal: HemaSphere (2023)

Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: Primary central nervous system lymphoma (PCNSL) has a very poor survival. The efficacy of high-dose methotrexate as a first-line treatment was suboptimal with a short remission time and low response rate. The discovery of the frequent 9p24.1/PD-L1/PD-L2 copy number alterations and increased expression of PD-L1 in PCNSL provide the rationale to evaluate the efficacy of PD-1antibody in PCNSL. Aims: To assess the efficacy and safety of penpulimab (an anti-PD1 antibody of IgG1 isotype) plus rituximab, methotrexate, and cytarabine (Pen-RMA) in patients with PCNSL. Targeted next-generation sequencing (NGS) was used to explore the characterization of genomic alterations of PCNSL, and circulation tumor DNA (ctDNA) of cerebrospinal fluid (CSF) was used to evaluate the efficacy of treatment and predict relapse. The primary objective of this study was 2-year PFS. Methods: NCT05347641 is a Phase II, single-center, single-arm, open-label study. An estimated 23 newly diagnosed PCNSL patients will be enrolled. Eligible patients are aged 18 to 75 years, and ECOG performance status of 0‒4. The Pen-RMA induction treatment includes rituximab 375 mg/m2, d0; methotrexate 3.5g/m2, d1; cytarabine 1‒2g/m2, q12h, d2‒3; penpulimab 200 mg, d5; 21d/cycle. After six cycles, patients who achieve CR/CRu/PR will undergo ASCT (for patients ≤ 60 yr), patients who achieve CR after ASCT will receive 8 cycles of penpulimab as maintenance therapy, and those who achieve PR will receive whole brain radiotherapy (WBRT) combined with 8 cycles of penpulimab. Patients over 60 yr who achieve CR will receive 8 cycles of penpulimab, and those who reach PR will receive WBRT combined with 8 cycles of penpulimab. Baseline tissue samples and sequential CSF/plasma samples are performed NGS in Nanjing Geneseeq Technology Inc. Results: Between 2022.04 and 2023.02, eighteen newly diagnosed PCNSL patients were enrolled. The median age was 64 (45‒74) yr, 15 patients (88.9%) scored 2‒4 of ECOG. The median cycles of treatment were 6 (1-6). Grade 3/4 hematologic toxicities included neutropenia (3, 18.8%) and thrombocytopenia (2, 12.5%). One patient had a Grade 3 renal dysfunction. The mutational profiles of baseline samples from 14 cases revealed the 2 frequent mutations of MYD88L265P and PIM1, 12 cases were classified into MCD subtype and 1 case was classified into BN2 subtype. Fifteen patients were evaluable after 3 cycles, 3 of them had disease progressed, the ORR was 80.0% (CRR was 66.7%). Of the 13 evaluable patients after 6 cycles, 10 patients have completed 6 cycles and they all reached CR (ORR was 76.9% and CRR was 76.9%). Five of them had entered the maintenance phase while 5 patients delayed maintenance due to COVID 19 pneumonia. The median follow-up time was 9.5 months (1‒11), the median PFS and OS were not reached. CSF ctDNA monitoring was performed in 6 patients after 6 cycles. Three of them had imaging CR and CSF ctDNA clearance. Three patients were assessed as CR by imaging after 6 cycles, but the CSF ctDNA was still positive, 2 of them relapsed while 1 patient had CSF ctDNA clearance during the maintenance phase (Figure 1). Summary/Conclusion: Our preliminary results suggested that the 9p24.1/PD-L1/PD-L2 copy number alterations were less than reported, but Pen-RMA also achieved excellent responses in newly diagnosed PCNSL patients with mild toxicity. CSF ctDNA could be leveraged to overcome the limitations of tissue biopsies for diagnosis and assessed more sensitively compared with imageology-based response evaluation.Figure 1. Swimmer’s plot for patients receiving Pen-RMA treatment. Keywords: Clinical trial, CNS lymphoma, ctDNA, Phase II